Continuous Production of Docetaxel-Loaded Nanostructured Lipid Carriers Using a Coaxial Turbulent Jet Mixer with Heating System
Abstract
The continuous synthesis of nanoparticles (NPs) has been actively studied due to its great potential to produce NPs with reproducible and controllable physicochemical properties. Here, we achieved the high throughput production of nanostructured lipid carriers (NLCs) using a coaxial turbulent jet mixer with an added heating system. This device, designed for the crossflow of precursor solution and non-solvent, combined with the heating system, efficiently dissolves solid lipids and surfactants. We reported the flow regime according to the Reynolds number (Re). Also, we confirmed the size controllability of NLCs as dependent on both Re and lipid concentration. The optimized synthesis yields NLCs around 80 nm, ideal for targeted drug delivery by enhanced permeability and retention (EPR) effect. The coaxial turbulent jet mixer enables effective mixing, producing uniform size distribution of NLCs. The NLCs prepared using the coaxial turbulent jet mixer were smaller, more uniform, and had higher drug loading compared to the NLCs synthesized by a bulk nanoprecipitation method, showcasing its potential for advancing nanomedicine.
Introduction
During the previous decades, the number of research papers reporting nanostructured lipid carrier (NLC)-based formulations has significantly increased. The rise in the NLC research is intrinsically attributed to various advantages including high drug loading, long-term drug stability, biocompatibility, biodegradability, ability to penetrate the blood–brain barrier (BBB), etc. [1,2,3,4,5] In most cases, the preparation of NLCs is conducted by a conventional bulk synthesis method under elevated temperatures to enhance the solubility of lipids and surfactants [4]. The conventional bulk synthesis for nanoparticles (NPs) is inherently discontinuous and suffers from the limited controllability and reproducibility of physicochemical properties [6,7,8]. These limitations impede scalable production and consistent quality, posing challenges for regulatory approval and clinical applications. To address these shortcomings, continuous microfluidic techniques have emerged as a potential solution. However, despite their promising advantages in improving controllability and reproducibility, microfluidic methods still face challenges in achieving mass production capabilities [9]. This bottleneck restricts their utility for clinical and industrial applications. The coaxial turbulent jet mixer has recently emerged as an innovative platform, offering controllability and reproducibility while enabling the large-scale continuous production of various nanoparticles including polymeric NPs, iron oxide NPs, and liposomes at ambient temperatures [5,10,11,12].
In parallel, docetaxel (DTX) has received significant attention for its incorporation into nanoparticle-based drug delivery systems due to its poor water solubility and systemic toxicity in free-drug form. Recent clinical research has highlighted the potential of DTX-containing nanoparticles in improving drug delivery efficiency, reducing side effects, and enhancing therapeutic outcomes. For example, DTX-loaded polymeric nanoparticles, such as BIND-014, have demonstrated improved pharmacokinetics and antitumor efficacy in early-phase clinical trials compared to traditional formulations [13,14]. These advances highlight the clinical relevance of developing scalable, reproducible, and efficient synthesis methods for DTX-loaded nanoparticles. However, to our best knowledge, no experimental study has been reported to synthesize NLCs by creating high-temperature environments in high throughput continuous production with the flash nanoprecipitation method.
In this study, we successfully expanded the capability of the coaxial turbulent jet mixer by incorporating a heating system, thereby achieving the high-temperature synthesis of NLCs while preserving the advantages of homogeneity, controllability, and reproducibility. The integration of a heating system involving hot plates adjacent to each pump minimizes temperature drops within the pumps, dampers, and tube fittings, thus elevating the temperature of both the surroundings and the device itself. As a result, NLC synthesis was achieved without the need for a separate temperature-controlled room. The effects of lipid concentration and Reynolds number (Re) were systematically changed to control the average NPs size and the polydispersity index (PDI). The optimized DTX-loaded NLC formulation with uniform size distribution was characterized for drug loading, encapsulation efficiency, and release profile. The DTX-loaded NLCs synthesized with the coaxial turbulent jet mixer exhibited higher drug loading and encapsulation efficiencies, ensuring improved therapeutic efficacy. Release profile analyses indicated comparable delayed release behavior between the DTX-loaded NLCs produced using the coaxial turbulent jet mixer and those from bulk methods, even though the DTX-loaded NLCs prepared using a coaxial turbulent jet mixer are significantly smaller. The combination of the coaxial turbulent jet mixer and the integrated heating system has enabled the large-scale and continuous production of NLCs with controlled size distribution and enhanced drug loading characteristics, which are crucial for evaluating their potential efficacy and stability for drug delivery applications.
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Materials
Compritol® 888 ATO was purchased from Gattefossé (Saint-Priest, France). Oleic acid, phenolphthalein, ethanol, and Kolliphor® P 407 were purchased from Sigma-Aldrich (St. Louis, MO, USA). Tetrahydrofuran (THF) was purchased from Honeywell (Charlotte, NC, USA). Sodium hydroxide (0.1 N) was purchased from Burdick & Jackson (Muskegon, MI, USA). Hydrogen chloride (0.1 N) was obtained from Daejung Chemicals (Siheung-si, Republic of Korea). DTX was purchased from LC Laboratories (Woburn, MA, USA). For imaging purposes, uranyl acetate was obtained from Electron Microscopy Sciences (Hatfield, PA, USA).
Lim, H.S.; Choi, W.I.; Lim, J.-M. Continuous Production of Docetaxel-Loaded Nanostructured Lipid Carriers Using a Coaxial Turbulent Jet Mixer with Heating System. Molecules 2025, 30, 279. https://doi.org/10.3390/molecules30020279
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